INVESTGATION OF NUCLEIC ACID BASE DERIVED TAMOXIFEN ANALOGUES FOR BREAST CANCER: In the USA, breast cancer is one of the major causes of death in women and a systemic approach such as chemotherapy is required for effective cancer management. It has been established that one of the primary causes of breast cancer is high levels of estrogen in women. Breast cancer drugs such asTamoxifen reduces the estrogen levels by blocking the estrogen receptor. Tamoxifen and other chemotherapeutic treatments for breast cancer also have serious toxic side effects due to their lack of selectivity to cancer cells. Therefore, there is a need for the development of newer agents with more selective and potent anticancer properties for the treatment of breast cancer. Tamoxifen, an estrogen antagonist, is a structural analogue of an earlier discoved drug, Diethystibestrol (DES), with estrogen agonist properties. Minor structural modifications in diethylstilbestrol led to the discovery of tamoxifen with antiestrogenic properties. Therefore, over the past decade we have been investigating nucleic acid base (purine or pyrimidine) derived diethystibestrol (DES) analogues as potential and selective anticancer agents with antiestrogenic properties similar to tamoxifen. Our biomedical investigation of these DES-purine and DES-pyrimidine analogues has yielded several 'leads'such as N9-(butenyl)purine, N9-(aryl)purine and N1- (aryl)pyrimidine compounds that have shown consistant preclinical anticancer activity at micromolar/nanomolar concentrations in several breast and other cancer cell lines. This promising anticancer activity may be due to the antagonist properties of DES-purines and DES-pyrimidines at the estrogen receptor. Therefore, we hypothesized that a nucleic acid base derived tamoxifen-purine and tamoxifen-pyrimidine analogues may exhibit a better ability to form an estrogen receptor-'purine'or 'pyrimidine'ligand complex that can repress gene transcription by signaling through the estrogen receptors and thus may exhibit improved anticancer activity than our current DES-nucleic acid base analogues. Therefore, in this project we describe the design, development and screening of new tamoxifen analogues with different pyrimidine and purine nucleic acid bases as potential estrogen receptor anatgonists for the treatment of breast cancer. The synthesis and characterization of all the proposed compounds will be carried out at the Xavier University of Louisiana, College of Pharmacy, New Orleans, LA. The screening of proposed compounds will be carried out at the National Cancer Institute (NCI), Bethesda, MD. The information gained in this project will be valuable not only in determining the structure-activity-relationship of this new class of compounds, but may also result in the development of a selective and potent agents for the treament of breast cancer.